With regard to the states of the arts in this field, for example, the following dihydropyridine compounds are known. ##STR1##
One object of this invention is to provide the new and useful dihydropyridine derivative and the pharmaceutically acceptable salt thereof, which are structurally characterized in the substituent(s) at the third and/or sixth positions of the dihydropiridine nucleus and have stronger activity as compared with the known compounds, for example, as shown above, especially in anti-hypertensive activity.
Another object of this invention is to provide processes for the preparation of the dihydropyridine derivative and the salt thereof.
A further object of this invention is to provide an useful pharmaceutical composition comprising, as an active ingredient, said dihydropyridine derivative or the pharmaceutically acceptable salt thereof, which is useful as a vasodilator and anti-hypertensive agents, especially, anti-hypertensive agent.
Still further object of the present invention is to provide a therapeutical method for treatment of cardiovascular disorder such as coronary insufficiency, angina pectoris or myocardial infarction and hypertension.
The dihydropyridine derivative of this invention can be represented by the formula: ##STR2## wherein R.sup.1 is nitro, halogen, lower alkoxycarbonyl, cyano, trihalo(lower)alkyl or phenyl,
R.sup.2 is lower alkyl; [N-lower alkyl-N-haloar(lower)alkyl]amino(lower)alkyl; [N-lower alkyl-N-lower alkylar(lower)alkyl]amino(lower)alkyl; [N-lower alkyl-N-lower alkoxyar(lower)alkyl]amino(lower)alkyl; aroylamino(lower)alkyl, saturated N-containing heterocyclic(lower)alkyl, in which the N-containing heterocyclic moiety is always linked by the nitrogen atom to the lower alkyl moiety; heterocyclic-thio(lower)alkyl; lower alkanoyloxy(lower)alkyl; lower alkylthio(lower)alkyl; ar(lower)alkylthio(lower)alkyl; or arylthio(lower)alkyl, PA1 R.sup.3 is lower alkyl, PA1 R.sup.4 is lower alkyl and PA1 R.sup.5 is cyano, formyl, di(lower)alkoxymethyl, hydroxymethyl, halo(lower)alkanoyloxymethyl, lower alkanoyloxymethyl, lower alkoxyaroyloxymethyl, heterocycliccarbonyloxymethyl, lower alkanoyl(lower)alken-1-yl, halo(lower)alken-1-yl, cyano(lower)alken-1-yl, hydroxy(lower)alken-1-yl or lower alkyn1-yl, PA1 provided that PA1 R.sub.a.sup.2 is halo(lower)alkyl, PA1 R.sub.b.sup.2 is [N-lower alkyl-N-haloar(lower)alkyl]-amino(lower)alkyl; [N-lower alkyl-N-lower alkylar(lower)alkyl]amino(lower)alkyl; [N-lower alkyl-N-lower alkoxyar(lower)alkyl]amino(lower)alkyl; aroylamino(lower)alkyl; saturated N-containing heterocyclic(lower)alkyl, in which the N-containing heterocyclic moiety is always linked by the nitrogen atom to the lower alkyl moiety; or heterocyclic-thio(lower)alkyl and PA1 R.sup.a is [N-lower alkyl-N-haloar(lower)alkyl]amino; [N-lower alkyl-N-lower alkylar(lower)alkyl]amino, N-lower alkyl-N-lower alkoxyar(lower alkyl)amino; aroylamino; saturated N-containing heterocyclic group; or heterocyclic-thio. PA1 R.sub.c.sup.2 is [N-lower alkyl-N-haloar(lower)alkyl]amino(lower)alkyl; ]N-lower alkyl-N-lower alkylar(lower)alkyl]amino(lower)alkyl; [N-lower alkyl-N-lower alkoxyar(lower)alkyl]amino(lower)alkyl; aroylamino(lower)alkyl; saturated N-containing heterocyclic-(lower)alkyl, in which the N-containing heterocyclic moiety is always linked by the nitrogen atom to the lower alkyl moiety; heterocyclicthio(lower)alkyl; lower alkanoyloxy(lower)alkyl; lower alkylthio(lower)alkyl, ar(lower)alkylthio(lower)alkyl or arylthio(lower)alkyl and PA1 R.sub.a.sup.5 is di(lower)alkoxymethyl. PA1 R.sub.d.sup.2 is [N-lower alkyl-N-haloar(lower)alkyl]amino(lower)alkyl; [N-lower alkylN-lower alkylar(lower)alkyl]amino(lower)alkyl; [N-lower alkyl-N-lower alkoxyar(lower)alkyl]amino(lower)alkyl; aroylamino(lower)alkyl; saturated N-containing heterocyclic-(lower)alkyl, in which the N-containing heterocyclic moiety is always linked by the nitrogen atom to the lower alkyl; heterocyclicthio(lower)alkyl; hydroxy(lower)alkyl; lower alkylthio(lower)alkyl; ar(lower)alkylthio(lower)alkyl, or arylthio(lower)alkyl. PA1 R.sub.b.sup.5 is formyl or lower alkanoyl(lower)alken-1-yl, and PA1 R.sub.c.sup.5 is hydroxymethyl or hydroxy(lower)alken-1-yl. PA1 R.sup.b is lower alkanoyl, halo(lower)alkanoyl, lower alkoxyaroyl or heterocyclic-carbonyl, provided that when R.sup.1 is nitro, halogen or trihalo(lower)alkyl and R.sup.2 is lower alkyl, then R.sup.b is halo(lower)alkanoyl, lower alkoxyaroyl or heterocyclic-carbonyl, and when R.sup.1 is cyano or lower alkoxycarbonyl, then R.sup.b is halo(lower)alkanoyl, lower alkanoyl, lower alkoxyaroyl or heterocycliccarbonyl. PA1 R.sub.d.sup.5 is lower alkanoyl(lower)alken-1-yl, halo(lower)alken-1-yl or cyano(lower)alken-1-yl, PA1 R.sup.c is aryl or lower alkyl, PA1 R.sup.d is hydrogen or halogen, and PA1 R.sup.e is lower alkanoyl, halogen or cyano. PA1 R.sub.e.sup.5 is lower alkyn-1-yl, and PA1 X is halogen. PA1 Compound A (reference compound): 2-(N-benzyl-N-methylamino)ethyl ester of 6-cyano-5-ethoxycarbonyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3- carboxylic acid. PA1 Compound B: 2-[N-(4-Chlorobenzyl)-N-methylamino]ethyl ester of 6-cyano-5-ethoxycarbonyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3- carboxylic acid. PA1 Compound C: Hydrochloride of 2-[N-(3,4-dichlorobenzyl)-N-methylamino]ethyl ester of 6-cyano-5-ethoxycarbonyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3- carboxylic acid, hydrochloride.
when PA2 then R.sup.5 is halo(lower)alkanoyloxymethyl, lower alkoxyaroyloxymethyl, heterocycliccarbonyloxymethyl, lower alkanoyl(lower)alken-1-yl, halo(lower)alken-1-yl, cyano(lower)alken-1-yl, hydroxy(lower)alken-1-yl or lower alkyn1-yl, and PA2 when R.sup.1 is cyano or lower alkoxycarbonyl and R.sup.2 is lower alkyl, PA2 then R.sup.5 is halo(lower)alkanoyloxymethyl, lower alkanoyloxymethyl, lower alkoxyaroyloxymethyl, heterocycliccarbonyloxymethyl, lower alkanoyl(lower)alken-1-yl, halo(lower)alken-1-yl, cyano(lower)alken-1-yl, hydroxy(lower)alken-1-yl or lower alkyn-1-yl,
R.sup.1 is nitro, halogen or trihalo(lower)alkyl and PA3 R.sup.2 is lower alkyl,
With regard to the object compound of the above formula (I), it is to be understood that the compound (I) represents inclusively all of the possible optical and/or geometrical isomers due to the asymmetric carbon atom(s) and/or carbon-carbon double bond in the group for R.sup.5 in the molecule of the compound (I), and accordingly such optical and/or geometrical isomers are also included within the scope of the present invention.
According to this invention, the object compound (I) can be prepared by the processes as illustrated by the following reaction schemes.